Induction of NAD(P)H:quinone oxidoreductase (QR) by tert-butylhydroquinone (tBHQ) prior to glutamate treatment significantly decreased glutamate-mediated cytotoxicity. Stable overexpression of QR, however, did not protect cells from glutamate-, dopamine or H2O2-induced apoptosis. Thus, the protection afforded by tBHQ is not due simply to an increase in QR, but the coordinate regulation of multiple genes by a common mechanism. Our laboratory has shown that tBHQ increases QR through activation of its antioxidant response element (ARE) in human neuroblastoma cells and primary glial cell cultures. We hypothesize that increased expression of ARE-driven genes block oxidative stress-induced cell death. The specific aims of this proposal are to: 1) Determine the molecular mechanism(s) by which tBHQ activates the ARE and increases QR in human neuroblstoma cells; 2) Characterize the expression pattern and regulation of the ARE in vivo; 3) Determine the effect of overexpresion of amyloid precursor protein on QR and ARE in transgenic mouse models of alzheimer's disease; 4) Characterize the expression pattern of QR in human brains from control and AD patients. Increased oxidative stress is associated with neuronal cell death following acute insults such as epilepsy, ischemia, and hypoglycemia. Oxidative stress is also believed to be a principle factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's Huntington's and Amyotrophic Lateral Sclerosis. Oxidative stress is an imbalance in which free radicals and their products exceed the capacity of antioxidant defense mechanisms. A gain in product formation and /or loss in protective mechanisms can disturb this equilibrium. Presently, we have little knowledge of how or by neurodegenerative diseases such as Alzheimer's disease (Specific Aims 3 and 4). Elucidating the molecular mechanisms (s) regulating ARE genes in brain, therefore, may be crucial for developing therapeutic approaches to mitigate, or prevent, neurotoxicity.